Protein kinases are a kind of phosphotransferases, and the role thereof is to transfer the gamma-phosphate group of ATP into a specific amino acid residue of a substrate to phosphorylate a protein, therefore exerting its physiological and biochemical functions. The protein kinases are an important class of kinases. In signal transduction, their main functions lie in two aspects: one is to regulate the activity of the protein by phosphorylation; the other is to amplify progressively the signal by progressive phosphorylation of protein so as to cause cellular reaction.
Abnormal protein kinase activity is not only closely related to the abnormity of certain steps in a series of intracellular signal transduction pathways, such as tumor proliferation, apoptosis and metastasis, but also the main reason that leads to a range of other human diseases related to inflammatory or proliferative response, such as rheumatoid arthritis, cardiovascular and neurological diseases, asthma, psoriasis. More than four hundred kinds of human diseases have been known to be related directly or indirectly to the protein kinase, which makes the protein kinase become another important class of drug targets after the G-protein-coupled receptors.
Protein kinase family consists of more than 500 members, which usually can be divided into two classes, i.e. the protein tyrosine kinases (PTKs) and serine-threonine kinases. In accordance with the location of the kinase in the cells, they can also be divided into receptor kinase and non-receptor kinase which is also known as the intracellular kinase. Receptor kinases generally belong to the tyrosine kinases and are also referred to as receptor tyrosine kinases (RTKs). Such a receptor kinase is composed of an extracellular portion, a transmembrane region and an intracellular portion. The portion of kinase having catalytic activity is located in the cytoplasm. The overwhelming majority of serine-threonine kinases are located within the cells and belong to non-receptor kinases, also called cytoplasmic kinases.
A typical representative of the RTKs family is growth factor receptors, which may be divided into at least 19 subfamilies. The following are several major subfamilies:
(a) HER family receptor tyrosine kinases, including EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. EGFR is the target of synthetic small molecules drug Tarceva®, Tykerb® and the monoclonal antibody Erbitux® for the treatment of non-small cell lung cancer.
(b) the subfamily consisting of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor-related receptor (IRR), wherein, IGF-1R is a well-established anti-cancer target, but because it is too similar with IR, especially in the intracellular kinase portion in which the amino acid sequence is 100% identical to the corresponding amino acid sequence of IR, it can inhibit the activity of the IGF-1R while typically inhibiting the activity of IR. There is evidence that IR is also an efficient anti-cancer target. However, it is necessary to find the balance of effectiveness and safety risks with regard to IR inhibitors for anti-cancer because the inhibition of IR leads to the risk of elevated blood sugar.
(c) Platelet-derived growth factor receptor (PDGFR) family, including PDGFR-α, PDGFR-β, CSF1R, c-KIT and c-fms, wherein the c-Kit is also the molecular target of the drug Gleevec® for treatment of leukemia treatment and is used to treat gastrointestinal stromal tumors.
(d) Vascular endothelial growth factor receptor (VEGFR) family, including FLT1 (Fms-like tyrosine kinase 1 or VEGFR1), KDR (or VEGFR-2) and FLT4 (or VEGFR3), the members of which are molecular targets for Sutent® and Naxavar®.
(e) Fibroblast growth factor receptor (FGFR) family, including FGFR1, FGFR2, FGFR3 and FGFR4 as well as seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, and FGF7, the members of which are still in clinical trials as molecular target drugs.
(f) MET family, including c-Met also known as human hepatocyte growth factor receptor (hHGFR) and RON, wherein c-Met plays an important role in the growth and metastasis of initial tumors. The members of the family are still in clinical trials as a molecular target drug.
(g) RET family. RET is a receptor of GDNF family members, having RET51, RET43 and RET9 isoforms. It is still in clinical trials as a molecular target drug.
(h) Eph family, being the biggest family of receptor tyrosine kinase and consisting of 16 receptors (EPHA1, EphA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). These members play an important role in the development of the animal and some members play a role in tumors.
AXL is another important receptor tyrosine kinase. AXL is also known as UFO/ARK/Tyro, and the ligand thereof is a vitamin K-dependent growth promoting factor GAS6. AXL is firstly found as transforming gene in chronic myeloid leukemia (CML). AXL is overexpressed in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer and melanoma Inhibition of AXL activity may play a role in inhibiting tumor growth, proliferation and metastasis.
The non-receptor kinase does not have the extracellular portion or the transmembrane region, and the entire kinase is in the cytoplasm. It is currently known that there are at least 24 kinds of non-receptor kinases which are divided into 11 subfamilies, i.e. Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and ACK subfamily. The Src subfamily is the biggest one, and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk kinase. For details, see Neet, K.; Hunter, T. Genes to Cells 1996, 1, 147-169, and the references cited therein. Although several non-receptor kinases are tyrosine kinases, the majority of non-receptor kinases are serine-threonine kinases. Several members therein are the molecular target for the drugs Gleevec® and Sprycel® for treatment of leukemia.
As mentioned above, the receptor kinases and non-receptor kinases have been proved as anti-tumor targets in the clinical and practical applications, and several anti-tumor drugs have been approved for marketing for treatment of patients. In addition to treatment of tumors, the abnormal activity of inhibition of receptor kinases and non-receptor kinases can also be used for treating the following diseases, including but not limited to psoriasis or serpedo, cirrhosis, diabetes, diseases involving angiogenesis, diseases involving restenosis, eye diseases, age-related macular degeneration, rheumatoid arthritis and other inflammation, immune system diseases such as autoimmune diseases, cardiovascular diseases such as atherosclerosis, kidney disease. Therefore it is necessary to continue to develop inhibitors of these kinases.
Histone deacetylase (HDAC) is a class of enzymes widely found in bacteria, fungi, plants and animals, whose role is to remove acetyl from the amino groups of the core histone N-terminal lysine residues, which causes the core histone N-terminal positively charged to enhance the combination with the negatively charged DNA, and thereby preventing the transcription machinery from contacting with the DNA template. According to their homology to fungal proteins, histone deacetylases (HDAC) are divided into four classes: class I includes HDAC1, HDAC2, HDAC3 and HDAC8, which are homologous to the fungal protein RPD3; class II includes HDAC4, HDAC5, HDAC7 and HDAC9 which are homologous to the fungal protein HDA1; class IIa includes HDAC6 and HDAC 10 containing two catalytic point; class IV includes HDAC11, the catalytic center thereof contains the amino acid residues shared with class I and II HDAC. The catalytic sites of the 11 HDAC isoforms have zinc ions, and may be inhibited by hydroxamic acid compounds such as SAHA (Vorinostat), trichostatin A (TSA). HDAC inhibitors as mood stabilizers and anti-epileptic drugs have a long history in psychiatry and neurology. HDAC inhibitors are investigated for use in treatment of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease. Another large class of applications of HDAC inhibitors are used as anticancer drugs, the representative example thereof is Vorinostat developed by Merck, which is approved by FDA for treatment of metastatic cutaneous T-cell lymphoma (CTCL) in 2006. The treatment of other tumors including solid tumors and leukemia by HDAC inhibitors is being in clinical trials.